POS1578 JAK INHIBITORS AND VEXAS SYNDROME: A SUCCESSFULLY CASE TREATED WITH FILGOTINIB
Authors: S. Bindoli, E. Bertoldo, A. Doria, C. Baggio, P. Sfriso
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> VEXAS syndrome is a novel described autoinflammatory entity for which the diagnosis is defined by somatic mutations in the <i>UBA1</i> X-linked gene in hematopoietic progenitor cells. The clinical manifestations are heterogeneous, ranging from autoinflammatory symptoms to the presence of underlying hematologic disorders. Response to treatment in VEXAS is very poor and to date the therapeutical strategies adopted are only partially effective. However, recently described cohorts of VEXAS patients treated with Janus-Kinases Inhibitors (JAK-I) demonstrated that these drugs can be effective for the treatment of several manifestations related to the disease. <h3>Objectives</h3> To describe the case of a 65-year-old man affected by VEXAS who was successfully treated with the selective JAK-1 inhibitor filgotinib. <h3>Methods</h3> We present the case of a 65-year-old man, diagnosed with a myelodysplastic syndrome (MDS grade 3, sec WHO, 2016) one year earlier, presenting with a recent history of leukocytoclastic vasculitis, deep vein thrombosis, tenosynovitis, and ear chondritis. He was admitted to the hospital for hyperpyrexia (39° TC), increased inflammatory markers, macrocytic anemia with Hb 7,7 g/l and MCV 104 fL and requiring multiple blood transfusions, and shortness of breath caused by a pleural effusion; after excluding neoplastic conditions, infections, and other potential mimickers (such as vasculitis), a genetic analysis was performed, revealing the somatic mutation Met41Leu (c.121A&gt;C) in the <i>UBA1</i> gene. Methylprednisolone was started from 16 mg/day (not reducible for recurrent flares). A peripheral blood smear was stained with May Grunwald-Giemsa staining to perform a cytogenic evaluation of leucocytes. Oil immersion microscopy with 1000× magnification was applied for the analysis. <h3>Results</h3> Following the diagnosis of VEXAS, the patient started filgotinib 200 mg/day, with a subsequent clinical and biological improvement that allowed for a slow reduction of glucocorticoids. After 1.5 month his laboratory exams showed: Hb 9,4 g/L, MCV 106 fL, C-reactive protein (CRP) 2,24 mg/dL. At peripheral blood smear, the patient had granulocytes with morphological changes, including cytoplasmic vacuoles (2%), immature neutrophils (29.8%) such as band neutrophils, hyposegmented neutrophils, and pseudo Pelger Huët-like morphology. Vacuolated/activated monocytes (4.5%) and nuclear abnormality (binucleated cells, buds) were also observed. <h3>Conclusion</h3> VEXAS syndrome is a new genetically-determined rare disease that requires a prompt treatment to avoid a rapid worsening. Glucocorticoids often represent the first line therapy and blood transfusion support is usually required; however, given the promising results derived from recently published cohorts, JAK-inhibitors, in particular selective JAK-1 (filgotinib, upadacitinib), or JAK1/2 blockers (ruxolitinib), may represent a suitable therapeutic approach. <h3>References</h3> [1]Beck DB, et al. Somatic Mutations in UBA1 and Severe Adult-Onset Autoinflammatory Disease. N Engl J Med. 2020;383(27). [2]Heiblig M, et al. Clinical Efficacy of JAK Inhibitors in Patients with Vexas Syndrome: A Multicenter Retrospective Study. Blood. 2021;138 <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> Sara Bindoli: None declared, Eugenia Bertoldo: None declared, Andrea Doria Speakers bureau: AstraZeneca, GSK, Ely Lilly, Chiara Baggio: None declared, Paolo Sfriso Speakers bureau: Novartis, Sobi.